Angiogenesis is the formation of new blood vessels from those which preexist within the body (1). It is of fundamental importance for the development of the embryo and a number of roles in post-natal life (e.g. wound healing, tissue regeneration, cyclical growth of the corpus luteum and endometrium). Angiogenesis is also important in a number of pathological conditions including the growth of solid tumors (1). Recent studies have suggested that the acquistion of an angiogenic-dependent phenotype is a key factor in the development of metastasis.
The introduction of techniques based on the polymerase chain reaction (PCR) for amplifying protein tyrosien kinase sequences has enabled the rapid isolation of novel members of the growth factor receptor family. Two of the putative receptors isolated NYK/flk-1 (2) (neuroepithelial kinase/fetal liver kinase) and tie2/Tek (3) have been shown to be expressed on endothelial cells and their precursors. NYK and its human equivalent KDR (4) have been shown to bind and be activated by the endothelial cell mitogen VEGF/VPF (vascular endothelial growth factor/vascular premeability factor) (5). VEGF has a mitagenic effect on endothelial cells but is also a potent mediator of vascular permeability. VEGF has in recent studies been shown to play a role in the hypoxia induced angiogenesis seen in a glioma model suggesting the VEGF may play a role in meadiating angiogenesis in other tumour systems (6). Other studies have shown that anti-VEGF monoclonal antibodies have an anti-tumour effect in vivo (7).
In work leading up to the present inventions the inventors developed a series of antibodies to the NYK (VEGF2R) receptor extracellular domain. These antibodies are useful in the development of a new range of therapeutic molecules such as agonists and antagonists of the NYK-VEGF interaction as well as a range of diagnostic agents capable of, for example, detecting normal or mutated NYK receptors, receptor expression on a cell surface and/or receptor-ligand interaction.